Methods and polymer compositions for treating retinal detachment and other ocular disorders

ABSTRACT

The invention provides methods and polymer compositions for treating retinal detachment and other ocular disorders, where the methods employ polymer compositions that can form a hydrogel in the eye of a subject. The hydrogel is formed by reaction of (i) a nucleo-functional polymer that is a biocompatible polymer containing a plurality of thio-functional groups —R1-SH wherein R1 is an ester-containing linker, such as a thiolated poly(vinyl alcohol) polymer and (ii) an electro-functional polymer that is a biocompatible polymer containing at least one thiol-reactive group, such as a poly(ethylene glycol) polymer containing alpha-beta unsaturated ester groups.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/952,209 filed Nov. 19, 2020, which is a divisional of U.S. patentapplication Ser. No. 16/245,397, filed on Jan. 11, 2019, now U.S. Pat.No. 10,874,767, which is a continuation of International Application No.PCT/US2017/041947, filed on Jul. 13, 2017, which claims the benefit ofand priority to United States Provisional Patent Application Ser. No.62/361,746, filed Jul. 13, 2016, the disclosures of each of which arehereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention provides methods and polymer compositions for treatingretinal detachment and other ocular disorders, where the methods employpolymer compositions that can form a hydrogel in the eye of a subject.

BACKGROUND

Disorders of the retina are a common cause of debilitating vision loss.Surgery can be required as part of a treatment regimen for variousdisorders of the retina, such as retinal detachments, retinal tears, andmacular holes. The first step in such surgeries is removal of thevitreous gel that fills the eye (i.e., a vitrectomy), thereby permittingsurgical access to the retinal tissue. At the end of these vitrectomies,an agent (i.e., a tamponade agent) is placed in the eye to apply forceto the retina and desirably seal any retinal breaks, thereby keepingretinal tissue in its desired location while the retina heals. Tamponadeagents commonly used in current medical practice include an expansivegas and silicone oil.

The currently available expansive gas and silicone oil tamponade agentshave multiple features that are undesirable. For example, patientstreated with an expansive gas tamponade agent must remain in a face-downposition for several weeks after surgery, the patients' post-operativevision quality is typically poor, and patients are generally notpermitted to travel by airplane or to high altitudes for several months.In addition, the expansive gas tamponade agent is often poorly effectivein supporting retinal tissue in the bottom half of the retina, whichposes a problem when the retinal pathology is located in the bottom halfof the retina. A silicone oil tamponade agent suffers the disadvantagesthat it substantially distorts the patient's vision, the patient mustundergo a second surgery to remove the silicone oil from the eye afterthe retinal tissue has healed, and oil applies a weaker tamponade forcerelative to gas.

The foregoing and other limitations of tamponade agents commonly used incurrent medical practice have prompted investigations into using othermaterials as a tamponade agent. Exemplary alternative materialsinvestigated for use as tamponade agents include, for example, variouspolymer materials such as described in, for example, Baino in Polymers(2010) vol. 2, pages 286-322; Crafoord et al. in Graefes Arch. Clin.Exp. Ophthalmol. (2011) vol. 249, pages 1167-1174; and U.S. Pat. No.9,072,809. However, it is difficult to achieve a polymer compositionthat can be easily administered to the eye, that once in eye providessufficient support/pressure on the entire retina, is not toxic to thepatient, is optically clear, and undergoes biodegradation at anappropriate rate so that the retinal tissue is supported for anappropriate amount of time to facilitate healing of retinal tissuefollowing a vitrectomy without having to perform a second surgery toremove the tamponade agent.

Accordingly, the need exists for new retinal tamponade agents andmethods for installing a retinal tamponade and/or treating retinaldetachment and other ocular disorders. The present invention addressesthis need and provides other related advantages.

SUMMARY

The invention provides methods and polymer compositions for treatingretinal detachment and other ocular disorders, where the methods employpolymer compositions that can form a hydrogel in the eye of a subject.The methods involve administering to the eye of the subject (i) anucleo-functional polymer that is a biocompatible polymer containing aplurality of thio-functional groups —R¹—SH wherein R¹ is anester-containing linker, and (ii) an electro-functional polymer that isa biocompatible polymer containing at least one thiol-reactive group,such as an alpha-beta unsaturated ester. The nucleo-functional polymerand electro-functional polymer are desirably low-viscosity materialsthat can be injected easily into the eye of a patient through anarrow-gauge needle, thereby permitting administration of the polymersthrough small surgical ports in the eye of the patient. This minimizestrauma to the patient's eye and is surgically feasible. Thenucleo-functional polymer and electro-functional polymer begin to reactspontaneously once mixed, where the vast majority of reaction betweenthe nucleo-functional polymer and electro-functional polymer occurswhile the polymers are in the patient's eye thereby forming a hydrogelin the eye of the patient that will apply pressure to and supportretinal tissue in the eye of the patient.

One exemplary advantage of the methods and polymer compositionsdescribed herein is that no toxic initiator agent or ultra-violet lightis required to facilitate reaction between the nucleo-functional polymerand electro-functional polymer. Additional exemplary advantages ofmethods and polymer compositions described herein is that reactionbetween the nucleo-functional polymer and electro-functional polymerdoes not generate byproducts or result in the formation of any medicallysignificant heat. Thus, the methods and polymer compositions describedherein are much safer than various polymer compositions described inliterature previously. Still further exemplary advantages of the methodsand polymer compositions described herein is that the polymers can beinserted through small surgical ports in the eye of the patient withoutcausing any significant degradation of the polymer, and the resultinghydrogel formed by reaction of the polymers is non-toxic and undergoesbiodegradation at a rate appropriate to support the retinal tissue overthe timeframe necessary for healing of the retinal tissue. Theappropriate biodegradation rate is advantageous because, for example,natural clearance of the hydrogel from the patient's eye at theappropriate time avoids having to perform a subsequent surgery to removethe hydrogel tamponade agent. Various aspects and embodiments of theinvention are described in further detail below, along with furtherdescription of multiple advantages provided by the invention.

Accordingly, one aspect of the invention provides a method of contactingretinal tissue in the eye of a subject with a hydrogel. The methodcomprises (a) administering to the vitreous cavity of an eye of thesubject an effective amount of a nucleo-functional polymer and anelectro-functional polymer; and (b) allowing the nucleo-functionalpolymer and the electro-functional polymer to react to form a hydrogelin the vitreous cavity; wherein the nucleo-functional polymer is abiocompatible polymer containing a plurality of thio-functional groups—R¹—SH wherein R¹ is an ester-containing linker, and theelectro-functional polymer is a biocompatible polymer containing atleast one thiol-reactive group. The nucleo-functional polymer and theelectro-functional polymer may be administered together as a singlecomposition to the vitreous cavity of the eye of the subject, oralternatively the nucleo-functional polymer and the electro-functionalpolymer may be administered separately to the vitreous cavity of the eyeof the subject. The method may be further characterized according, forexample, the identity of the nucleo-functional polymer,electro-functional polymer, and physical characteristics of the hydrogelformed therefrom, as described in the detailed description below.Exemplary subjects that may benefit from the method include, forexample, subjects having a physical discontinuity in the retinal tissue,such as subjects having a tear in the retinal tissue, a break in theretinal tissue, or a hole in the retinal tissue. In certain embodiments,the subject has undergone surgery for a macular hole or has undergone avitrectomy for vitreomacular traction. In certain other embodiments, thesubject has undergone surgery to repair a serous retinal detachment, torepair a tractional retinal detachment, or to remove at least a portionof an epiretinal membrane.

Another aspect of the invention provides a method of supporting retinaltissue in the eye of a subject, the method comprising: (a) administeringto the vitreous cavity of an eye of the subject an effective amount of anucleo-functional polymer and an electro-functional polymer; and (b)allowing the nucleo-functional polymer and the electro-functionalpolymer to react to form a hydrogel in the vitreous cavity; wherein thenucleo-functional polymer is a biocompatible polymer containing aplurality of thio-functional groups —R¹—SH wherein R¹ is anester-containing linker, and the electro-functional polymer is abiocompatible polymer containing at least one thiol-reactive group. Thenucleo-functional polymer and the electro-functional polymer may beadministered together as a single composition to the vitreous cavity ofthe eye of the subject, or alternatively the nucleo-functional polymerand the electro-functional polymer may be administered separately to thevitreous cavity of the eye of the subject. The method may be furthercharacterized according, for example, the identity of thenucleo-functional polymer, electro-functional polymer, and physicalcharacteristics of the hydrogel formed therefrom, as described in thedetailed description below. Exemplary subjects that may benefit from themethod include, for example, subjects having a physical discontinuity inthe retinal tissue, such as subjects having a tear in the retinaltissue, a break in the retinal tissue, or a hole in the retinal tissue.In certain embodiments, the subject has undergone surgery for a macularhole or has undergone a vitrectomy for vitreomacular traction. Incertain other embodiments, the subject has undergone surgery to repair aserous retinal detachment, to repair a tractional retinal detachment, orto remove at least a portion of an epiretinal membrane.

Another aspect of the invention provides a method of treating a subjectwith a retinal detachment, the method comprising: (a) administering aneffective amount of a nucleo-functional polymer and anelectro-functional polymer to the vitreous cavity of an eye of thesubject with a detachment of at least a portion of retinal tissue; and(b) allowing the nucleo-functional polymer and the electro-functionalpolymer to react to form a hydrogel in the vitreous cavity; wherein thehydrogel supports the retinal tissue during reattachment of the portionof the retinal tissue, the nucleo-functional polymer is a biocompatiblepolymer containing a plurality of thio-functional groups —R¹—SH whereinR¹ is an ester-containing linker, and the electro-functional polymer isa biocompatible polymer containing at least one thiol-reactive group.The nucleo-functional polymer and the electro-functional polymer may beadministered together as a single composition to the vitreous cavity ofthe eye of the subject, or alternatively the nucleo-functional polymerand the electro-functional polymer may be administered separately to thevitreous cavity of the eye of the subject. The method may be furthercharacterized according, for example, the identity of thenucleo-functional polymer, electro-functional polymer, and physicalcharacteristics of the hydrogel formed therefrom, as described in thedetailed description below. The retinal detachment may be, for example,a rhegmatogenous retinal detachment, a tractional retinal detachment, ora serous retinal detachment.

Another aspect of the invention provides an injectable, ocularformulation for forming a hydrogel in the eye of a subject, theformulation comprising: (a) a nucleo-functional polymer that is abiocompatible polymer containing a plurality of thio-functional groups—R¹—SH wherein R¹ is an ester-containing linker; (b) anelectro-functional polymer that is a biocompatible polymer containing atleast one thiol-reactive group; and (c) a liquid pharmaceuticallyacceptable carrier for administration to the eye of a subject. Suchinjectable, ocular formulation for forming a hydrogel may be used in themethods described herein.

The nucleo-functional polymer may be, for example, a biocompatiblepolymer selected from a polyalkylene and polyheteroalkylene polymer eachbeing substituted by (i) a plurality of thio-functional groups —R¹—SH,and optionally (ii) one or more hydroxyl, alkyl ester, hydroxyalkylester, or amide groups. In certain embodiments, the nucleo-functionalpolymer is a biocompatible poly(vinyl alcohol) polymer comprising:

wherein a is an integer from 1-10 and b is an integer from 1-10.

The electro-functional polymer may be, for example, a biocompatiblepolymer selected from a polyalkylene and polyheteroalkylene polymer eachbeing substituted by at least one thiolreactive group. In certainembodiments, the thiol-reactive group is —OC(O)CH═CH₂. In yet otherembodiments, the electro-functional polymer has the formula:

wherein R* is independently for each occurrence hydrogen, alkyl, aryl,or aralkyl; and m is an integer in the range of 5 to 15,000.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a GPC chromatograph showing exemplary starting materials(i.e., TPVA and PEGDA) and degradation products of a hydrogel subjectedto degradation conditions, as further described in Example 1 where thehydrogel was formed by reaction of thiolated poly(vinyl alcohol) andpoly(ethylene glycol)-diacrylate.

FIG. 2 is a ¹H NMR (D₂0) spectrum of thiolated poly (vinyl alcohol)polymer, as further described in Example 2.

FIG. 3 is an absorbance spectrum taken on a sample of test hydrogel, asfurther described in Example 2.

FIG. 4 is a graph showing results of a rheological properties analysisof test hydrogel, as further described in Example 4.

FIG. 5 is an illustration of hydrogel premix that has been dispensedfrom the syringe into a container, as further described in Example 5.

FIG. 6 is an illustration of a hydrogel that formed in a container,where the container is held in a vertical position, as further describedin Example 5.

FIG. 7 is an illustration of histopathologic analysis of rabbit retinaltissue obtained on day 7 after intravitreal injection for rabbit eyesthat (i) had received hydrogel premix (“hydrogel—treated eye”) and (ii)had not received hydrogel premix (i.e., “control”), as further describedin Example 7.

FIG. 8 is an illustration of a rabbit eye following a vitrectomy usingthe hydrogel according to procedures described in Example 8.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods and polymer compositions for treatingretinal detachment and other ocular disorders, where the methods employpolymer compositions that can form a hydrogel in the eye of a subject.The methods involve administering to the eye of the subject (i) anucleo-functional polymer that is a biocompatible polymer containing aplurality of thio-functional groups —R¹—SH wherein R¹ is anester-containing linker, and (ii) an electro-functional polymer that isa biocompatible polymer containing at least one thiol-reactive group,such as an alpha-beta unsaturated ester. The nucleo-functional polymerand electro-functional polymer are desirably low-viscosity materialsthat can be injected easily into the eye of a patient through anarrow-gauge needle, thereby permitting administration of the polymersthrough small surgical ports in the eye of the patient. This minimizestrauma to the patient's eye. The nucleo-functional polymer andelectro-functional polymer begin to react spontaneously once mixed,where the vast majority of reaction between the nucleo-functionalpolymer and electro-functional polymer occurs while the polymers are inthe patient's eye thereby forming a hydrogel in the eye of the patientthat will apply pressure to and support retinal tissue in the eye of thepatient.

One exemplary advantage of the methods and polymer compositionsdescribed herein is that no toxic initiator agent or ultra-violet lightis required to facilitate reaction between the nucleo-functional polymerand electro-functional polymer. Additional exemplary advantages ofmethods and polymer compositions described herein is that reactionbetween the nucleo-functional polymer and electro-functional polymerdoes not generate byproducts or result in the formation of any medicallysignificant heat. Thus, the methods and polymer compositions describedherein are much safer than various polymer compositions described inliterature previously. Still further exemplary advantages of the methodsand polymer compositions described herein is that the polymers can beinserted through small surgical ports in the eye of the patient withoutcausing any significant degradation of the polymer, and the resultinghydrogel formed by reaction of the polymers is nontoxic and undergoesbiodegradation at a rate appropriate to support the retinal tissue overthe timeframe necessary for healing of the retinal tissue. Theappropriate biodegradation rate is advantageous because, for example,natural clearance of the hydrogel from the patient's eye at theappropriate time avoids having to perform a subsequent surgery to removethe hydrogel tamponade agent.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section.

I. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₄₋₈cycloalkyl,” derivedfrom a cycloalkane. Exemplary cycloalkyl groups include, but are notlimited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. Unless specified otherwise, the aromatic ring may besubstituted at one or more ring positions with, for example, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl,—CO₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido,sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroarylmoieties, —CF₃, —CN, or the like. The term “aryl” also includespolycyclic ring systems having two or more carbocyclic rings in whichtwo or more carbons are common to two adjoining rings (the rings are“fused rings”) wherein at least one of the rings is aromatic, e.g., theother cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls,and/or aryls. In certain embodiments, the aromatic ring is substitutedat one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl.In certain other embodiments, the aromatic ring is not substituted,i.e., it is unsubstituted.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl,alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Theterm “heteroaryl” also includes polycyclic ring systems having two ormore rings in which two or more carbons are common to two adjoiningrings (the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, and/or aryls. In certain embodiments, theheteroaryl ring is substituted at one or more ring positions withhalogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, theheteroaryl ring is not substituted, i.e., it is unsubstituted.

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and orthodimethylbenzene are synonymous.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated 3- to 10-membered ringstructures, alternatively 3- to 7-membered rings, whose ring structuresinclude one to four heteroatoms, such as nitrogen, oxygen, and sulfur.The number of ring atoms in the heterocyclyl group can be specifiedusing C_(x)-C_(x) nomenclature where x is an integer specifying thenumber of ring atoms. For example, a C₃-C₇heterocyclyl group refers to asaturated or partially unsaturated 3- to 7-membered ring structurecontaining one to four heteroatoms, such as nitrogen, oxygen, andsulfur. The designation “C₃-C₇” indicates that the heterocyclic ringcontains a total of from 3 to 7 ring atoms, inclusive of any heteroatomsthat occupy a ring atom position. One example of a C₃heterocyclyl isaziridinyl. Heterocycles may also be mono-, bi-, or other multi-cyclicring systems. A heterocycle may be fused to one or more aryl, partiallyunsaturated, or saturated rings. Heterocyclyl groups include, forexample, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl,dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl,imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl,tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl,thiazolidinyl, thiolanyl, thiomorpholinyl, thiopyranyl, xanthenyl,lactones, lactams such as azetidinones and pyrrolidinones, sultams,sultones, and the like. Unless specified otherwise, the heterocyclicring is optionally substituted at one or more positions withsubstituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy,cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato,phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.In certain embodiments, the heterocyclyl group is not substituted, i.e.,it is unsubstituted.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety represented by thegeneral formula —N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independentlyrepresent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl,aralkyl, or —(CH₂)_(m)—R⁶¹; or R⁵⁰ and R⁵¹, taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ eachindependently represent hydrogen, alkyl, alkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₆₁, where m and R₆₁ are described above.

The term “amide” or “amido” as used herein refers to a radical of theform —R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, —C(O)NR_(b)R_(c), or—C(O)NH₂, wherein R_(a), R_(b) and R_(c) are each independently alkoxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, or nitro. The amide can beattached to another group through the carbon, the nitrogen, R_(b),R_(c), or R_(a). The amide also may be cyclic, for example R_(b) andR_(c), R_(a) and R_(b), or R_(a) and R_(c) may be joined to form a 3- to12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-memberedring.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating,ameliorating or eliminating, that results in the improvement of thecondition, disease, disorder, and the like, or ameliorating a symptomthereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. In certainembodiments, the pharmaceutically acceptable carrier is, or comprises,balanced salt solution. The compositions also can include stabilizersand preservatives. For examples of carriers, stabilizers and adjuvants,see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., MackPubl. Co., Easton, Pa. [1975]. The compositions may optionally contain adye. Accordingly, in certain embodiments, the composition furthercomprises a dye.

Throughout the description, the molecular weight of a polymer isweight-average molecular weight unless the context clearly indicatesotherwise, such as clearly indicating that the molecular weight of thepolymer is the number-average molecular weight.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. Therapeutic Methods and Injectable, Ocular Formulations for Forminga Hydrogel

The invention provides methods and polymer compositions for treatingretinal detachment and other ocular disorders, where the methods employpolymer compositions that can form a hydrogel in the eye of a subject.The methods include, for example, methods for contacting retinal tissuein the eye of a subject with a hydrogel, methods for supporting retinaltissue, methods for treating a subject with a retinal detachment, andmethods for treating hypotony, methods for treating a choroidaleffusion, methods for supporting tissue in or adjacent to the anteriorchamber of the eye, and methods of maintaining or expanding anasolacrimal duct, and injectable, ocular formulations for forming ahydrogel. The methods and compositions are described in more detailbelow.

First Method—Contacting Retinal Tissue in the Eye of a Subject with aHydrogel

One aspect of the invention provides a method of contacting retinaltissue in the eye of a subject with a hydrogel. The method comprises (a)administering to the vitreous cavity of an eye of the subject aneffective amount of a nucleo-functional polymer and anelectro-functional polymer; and (b) allowing the nucleo-functionalpolymer and the electro-functional polymer to react to form a hydrogelin the vitreous cavity; wherein the nucleo-functional polymer is abiocompatible polymer containing a plurality of thio-functional groups—R¹—SH wherein R¹ is an ester-containing linker, and theelectro-functional polymer is a biocompatible polymer containing atleast one thiol-reactive group.

The method can be further characterized by, for example, the identity ofthe subject. In certain embodiments, subject has a physicaldiscontinuity in the retinal tissue. In certain embodiments, thephysical discontinuity is a tear in the retinal tissue, a break in theretinal tissue, or a hole in the retinal tissue. In other embodiments,the subject has undergone surgery for a macular hole, has undergonesurgery to remove at least a portion of a epiretinal membrane, or hasundergone a vitrectomy for vitreomacular traction. In other embodiments,the subject has a detachment of at least a portion of the retinaltissue. The retinal detachment may be, for example, a rhegmatogenousretinal detachment. Alternatively, the retinal detachment may betractional retinal detachment or serous retinal detachment.

The nucleo-functional polymer and an electro-functional polymer areadministered to the eye of the subject in an amount effective to producea hydrogel that contacts retinal tissue. This effective amount may varydepending on the volume of the eye cavity to be filled, such that alarge eye cavity will require more nucleo-functional polymer and anelectro-functional polymer to produce a hydrogel occupying more volume,as can be readily determined by those of skill in the art based on theteachings provided herein.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Second Method—Supporting Retinal Tissue

Another aspect of the invention provides a method of supporting retinaltissue in the eye of a subject, the method comprising: (a) administeringto the vitreous cavity of an eye of the subject an effective amount ofnucleo-functional polymer and an electro-functional polymer; and (b)allowing the nucleo-functional polymer and the electro-functionalpolymer to react to form a hydrogel in the vitreous cavity; wherein thenucleo-functional polymer is a biocompatible polymer containing aplurality of thio-functional groups —R¹—SH wherein R¹ is anester-containing linker, and the electro-functional polymer is abiocompatible polymer containing at least one thiol-reactive group.

The method can be further characterized by, for example, the identity ofthe subject. In certain embodiments, subject has a physicaldiscontinuity in the retinal tissue. In certain embodiments, thephysical discontinuity is a tear in the retinal tissue, a break in theretinal tissue, or a hole in the retinal tissue. In other embodiments,the subject has undergone surgery for a macular hole, has undergonesurgery to remove at least a portion of a epiretinal membrane, or hasundergone a vitrectomy for vitreomacular traction. In other embodiments,the subject has a detachment of at least a portion of the retinaltissue. The retinal detachment may be, for example, a rhegmatogenousretinal detachment. Alternatively, the retinal detachment may betractional retinal detachment or serous retinal detachment.

The nucleo-functional polymer and an electro-functional polymer areadministered to the eye of the subject in an amount effective to supportthe retinal tissue, such as an amount that upon formation of thehydrogel, the hydrogel contacts the retinal tissue.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Third Method—Treating a Subject with a Retinal Detachment

Another aspect of the invention provides a method of treating a subjectwith a retinal detachment, the method comprising: (a) administering anucleo-functional polymer and an electro-functional polymer to thevitreous cavity of an eye of the subject with a detachment of at least aportion of retinal tissue; and (b) allowing the nucleo-functionalpolymer and the electro-functional polymer to react to form a hydrogelin the vitreous cavity; wherein the hydrogel supports the retinal tissueduring reattachment of the portion of the retinal tissue, thenucleo-functional polymer is a biocompatible polymer containing aplurality of thio-functional groups —R¹—SH wherein R is anester-containing linker, and the electro-functional polymer is abiocompatible polymer containing at least one thiol-reactive group.

The method can be further characterized by, for example, the nature ofthe retinal detachment. In certain embodiments, the retinal detachmentis a rhegmatogenous retinal detachment. In other embodiments, thesubject has tractional retinal detachment or serous retinal detachment.

The nucleo-functional polymer and an electro-functional polymer areadministered to the eye of the subject in an amount effective to supportthe retinal tissue, thereby facilitating treatment of the retinaldetachment.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Fourth Method—Treating Hypotony

Another aspect of the invention provides a method of treating a subjectwith low pressure in the eye (i.e., hypotony), the method comprising:(a) administering an effective amount of a nucleo-functional polymer andan electro-functional polymer to the vitreous cavity of an eye of thesubject; and (b) allowing the nucleo-functional polymer and theelectro-functional polymer to react to form a hydrogel in the vitreouscavity; to thereby treat the subject with low pressure in the eye,wherein the nucleo-functional polymer is a biocompatible polymercontaining a plurality of thio-functional groups —R¹—SH wherein R¹ is anester-containing linker, and the electro-functional polymer is abiocompatible polymer containing at least one thiol-reactive group. Incertain embodiments, the method causes an increase in pressure of atleast about 1 mmHg, 2 mmHg, 5 mmHg, 7 mmHg, or 10 mmHg in the eye of thesubject.

In certain embodiments, the subject suffers from a choroidal effusion(e.g., a serous choroidal effusion or hemorrhagic choroidal effusion).

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Fifth Method—Treating Choroidal Effusion

Another aspect of the invention provides a method of treating achoroidal effusion, the method comprising: (a) administering aneffective amount of a nucleo-functional polymer and anelectro-functional polymer to an eye of the subject having a choroidaleffusion; and (b) allowing the nucleo-functional polymer and theelectro-functional polymer to react to form a hydrogel; to thereby treatthe choroidal effusion, wherein the nucleo-functional polymer is abiocompatible polymer containing a plurality of thio-functional groups—R¹—SH wherein R¹ is an ester-containing linker, and theelectro-functional polymer is a biocompatible polymer containing atleast one thiolreactive group.

In certain embodiments, the choroidal effusion is a serous choroidaleffusion or hemorrhagic choroidal effusion.

In certain embodiments, the method causes an increase in pressure of atleast about 1 mmHg, 2 mmHg, 5 mmHg, 7 mmHg, or 10 mmHg in the eye of thesubject.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Sixth Method—Improving Visual Performance

Another aspect of the invention provides a method of improving visualperformance in a patient suffering from a retinal detachment, the methodcomprising: (a) administering to the vitreous cavity of an eye of thesubject an effective amount of nucleo-functional polymer and anelectro-functional polymer; and (b) allowing the nucleo-functionalpolymer and the electro-functional polymer to react to form a hydrogelin the vitreous cavity; wherein the nucleo-functional polymer is abiocompatible polymer containing a plurality of thio-functional groups—R¹—SH wherein R¹ is an ester-containing linker, and theelectro-functional polymer is a biocompatible polymer containing atleast one thiol-reactive group.

The method can be further characterized by, for example, the identity ofthe subject. In certain embodiments, the subject may have suffered froma retinal detachment that is a rhegmatogenous retinal detachment.Alternatively, the retinal detachment may be tractional retinaldetachment or serous retinal detachment.

The nucleo-functional polymer and an electro-functional polymer areadministered to the eye of the subject in an amount effective to supportthe retinal tissue, such as an amount that upon formation of thehydrogel, the hydrogel contacts the retinal tissue.

Visual performance pertains to the patient's overall vision quality andincludes a patient's ability to see clearly, as well as ability todistinguish between an object and its background. One aspect of visualperformance is visual acuity, which is a measure of a patient's abilityto see clearly. Visual acuity can be assessed, for example, by usingconventional “eye charts” in which visual acuity is evaluated by theability to discern letters of a certain size, with five letters of agiven size present on each line (see, e.g., the “ETDRS” eye chartdescribed in the Murphy, R. P., CURRENT TECHNIQUES IN OPHTHALMIC LASERSURGERY, 3rd Ed., edited by L. D. Singerman, and G. Cascas, ButterworthHeinemann, 2000). Evaluation of visual acuity may also be achieved bymeasuring reading speed and reading time. Visual acuity may be measuredto evaluate whether administration of a necrosis inhibitor and/or anapoptosis inhibitor to the affected eye preserves or permits improvementof visual acuity (e.g., to 20/40 vision or to 20/20 vision). In certainembodiments, a Snellen chart can be used to measure a patient's visualacuity, and the measurement can be taken under conditions that testlow-contrast visual acuity or under conditions that test high-contrastvisual acuity. Also, the visual acuity measurement can be taken underscotopic conditions, mesopic conditions, and/or photopic conditions.

Another aspect of visual performance is contrast sensitivity, which is ameasure of the patient's ability to distinguish between an object andits background. The contrast sensitivity can be measured under variouslight conditions, including, for example, photopic conditions, mesopicconditions, and scotopic conditions. In certain embodiments, thecontrast sensitivity is measured under mesopic conditions.

In certain embodiments, the improvement in visual performance providedby the method is improved visual acuity. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under scotopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under photopic conditions. In certain embodiments, theimprovement in visual acuity is a two-line improvement in the patient'svision as measured using the Snellen chart. In certain otherembodiments, the improvement in visual acuity is a one-line improvementin the patient's vision as measured using the Snellen chart.

In certain embodiments, the improvement in visual performance providedby the method is improved contrast sensitivity. The improvement incontrast sensitivity can be measured under various light conditions,such as photopic conditions, mesopic conditions, and scotopicconditions. In certain embodiments, the improvement in visualperformance provided by the method is improved contrast sensitivityunder photopic conditions. In certain embodiments, the improvement invisual performance provided by the method is improved contrastsensitivity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedcontrast sensitivity under scotopic conditions.

Results achieved by the methods can be characterized according to thepatient's improvement in contrast sensitivity. For example, in certainembodiments, the improvement in contrast sensitivity is at least a 10%,20%, 30%, 50%, 60%, 70%, 80%, 90%, or 100% improvement measured undermesopic conditions using an art-recognized test, such as a HolladayAutomated Contrast Sensitivity System. In certain embodiments, theimprovement in contrast sensitivity is at least a 10%, 20%, 30%, 50%,60%, 70%, 80%, 90%, or 100% improvement measured under photopicconditions using an art-recognized test, such as a Holladay AutomatedContrast Sensitivity System. In certain other embodiments, theimprovement in contrast sensitivity is at least a 10%, 20%, 30%, 50%,60%, 70%, 80%, 90%, or 100% improvement measured under mesopicconditions or scotopic conditions using an art-recognized test, such aHolladay Automated Contrast Sensitivity System.

Visual performance may also be measured by determining whether there isan increase in the thickness of the macula (e.g., macula thickness is15% thicker than, 35% thicker than, 50% thicker than, 60% thicker than,70% thicker than, or 80% thicker than a macula without the treatment asmeasured by optical coherence tomography (OCT); an improvement of thephotoreceptor cell layer or its subdivisions as seen in the OCT; animprovement of visual field (e.g., by at least 10% in the mean standarddeviation on the Humphrey Visual Field Test; an improvement of anelectroretinograph (ERG), a measurement of the electrical response ofthe retina to light stimulation, (e.g., to increase ERG amplitude by atleast 15%); and or preservation or improvement of multifocal ERG, whichevaluates the response of the retina to multifocal stimulation andallows characterization of the function of a limited area of the retina.

Visual performance may also be measured by electrooculography (EOG),which is a technique for measuring the resting potential of the retina.EOG is particularly useful for the assessment of RPE function. EOG maybe used to evaluate whether administration of a necrosis inhibitorand/or an apoptosis inhibitor to the retina of the affected eyepreserves or permits improvement in, for example, the Arden ratio (e.g.,an increase in Arden ratio of at least 10%).

Visual performance may also be assessed through fundus autofluorescence(AF) imaging, which is a clinical tool that allows evaluation of theinteraction between photoreceptor cells and the RPE. For example,increased fundus AF or decreased fundus AF has been shown to occur inAMD and other ocular disorders. Fundus AF imaging may be used toevaluate whether administration of a necrosis inhibitor and/or anapoptosis inhibitor to the retina of the affected eye slows diseaseprogression.

Visual performance may also be assessed by microperimetry, whichmonitors retinal visual function against retinal thickness or structureand the condition of the subject's fixation over time. Microperimetrymay be used to assess whether administration of a necrosis inhibitorand/or an apoptosis inhibitor to the retina of the affected eyepreserves or permits improvement in retinal sensitivity and fixation.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Seventh Method—Supporting Tissue in or Adjacent to the Anterior Chamberof the Eye

Another aspect of the invention provides a method of supporting tissuein or adjacent to the anterior chamber of the eye of a subject, themethod comprising: (a) administering an effective amount of anucleo-functional polymer and an electro-functional polymer to theanterior chamber of an eye of the subject; and (b) allowing thenucleo-functional polymer and the electro-functional polymer to react toform a hydrogel in the anterior chamber; wherein the nucleo-functionalpolymer is a biocompatible polymer containing a plurality ofthio-functional groups —R¹—SH wherein R¹ is an ester-containing linker,and the electro-functional polymer is a biocompatible polymer containingat least one thiol-reactive group. In certain embodiments, the methodsupports a graft in the anterior chamber of the eye. The hydrogelachieves supporting tissue in or adjacent to the anterior chamber of theeye by coming into contact with such tissue and optionally exerting aforce (e.g., 0.1, 0.5, 1.0, or 2.0 N) against such tissue.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Eighth Method—Maintaining or Expanding a Nasolacrimal Duct

Another aspect of the invention provides a method of maintaining orexpanding a nasolacrimal duct in a subject, the method comprising: (a)administering an effective amount of a nucleo-functional polymer and anelectro-functional polymer to a nasolacrimal duct in a subject; and (b)allowing the nucleo-functional polymer and the electro-functionalpolymer to react to form a hydrogel in the nasolacrimal duct; whereinthe nucleo-functional polymer is a biocompatible polymer containing aplurality of thio-functional groups —R¹—SH wherein R¹ is anester-containing linker, and the electro-functional polymer is abiocompatible polymer containing at least one thiolreactive group. Thehydrogel achieves maintaining or expanding a nasolacrimal duct by cominginto contact with such tissue and optionally exerting a force (e.g.,0.1, 0.5, 1.0, or 2.0 N) against such tissue.

The method can also be further characterized by, for example, theidentity of the nucleo-functional polymer, the identity of theelectro-functional polymer, physical characteristics of the hydrogelformed, and other features described herein below.

Injectable, Ocular Formulation for Forming a Hydrogel

Another aspect of the invention provides an injectable, ocularformulation for forming a hydrogel in the eye of a subject, theformulation comprising: (a) a nucleo-functional polymer that is abiocompatible polymer containing a plurality of thio-functional groups—R¹—SH wherein R¹ is an ester-containing linker; (b) anelectro-functional polymer that is a biocompatible polymer containing atleast one thiol-reactive group; and (c) a liquid pharmaceuticallyacceptable carrier for administration to the eye of a subject. Theformulation can be further characterized by, for example, the identityof the nucleo-functional polymer, the identity of the electro-functionalpolymer, physical characteristics of the hydrogel formed, and otherfeatures described herein below.

General Features of the Methods and Injectable Ocular Formulation

General features of the methods and injectable ocular formulation aredescribed below.

Features of the Hydrogel

The therapeutic methods and compositions for forming hydrogels can befurther characterized according to features of the hydrogel. Exemplaryfeatures of the hydrogel include, for example, refractive index,transparency, density, gelation time, elastic modulus, viscosity (e.g.,dynamic viscosity), biodegradation, and pressure generated by thehydrogen within the eye or other location into which the polymers forforming a hydrogel are inserted.

The hydrogel is formed by reaction of the nucleo-functional polymer andelectro-functional polymer, and the subsequent update of water from thesubject (e.g., the subject's eye). In the more specific embodiment of athiolated poly(vinyl alcohol) polymer as the nucleo-functional polymerand a poly(ethylene glycol) (PEG) containing thiol-reactive groups asthe electro-functional polymer, the hydrogel is formed by across-linking reaction of thiolated poly(vinyl alcohol) (TPVA) withpoly(ethylene glycol) (PEG) containing thiol-reactive groups. Thethiolated poly(vinyl alcohol) polymer can be prepared according toprocedures described in the literature (see, for example, U.S. PatentApplication Publication No. 2016/0009872, which is hereby incorporatedby reference), whereby thiol groups are incorporated intopoly(vinylalcohol) (PVA) by coupling thiol functionalities to thehydroxyl groups of the poly(vinyl alcohol), or through use of protectedthiol functionalities with subsequent deprotection. Certainpoly(ethylene glycol) polymers containing thiol-reactive groups (e.g.,an acrylate, methacrylate, maleimidyl, or N-hydroxysuccinimidyl) havebeen described in the literature (see, for example, U.S. PatentApplication Publication No. 2016/0009872).

Crosslinking of the thiolated poly(vinyl alcohol) and the poly(ethyleneglycol) containing thiol-reactive groups occurs through a Michaeladdition, without formation of byproducts and does not require use oftoxic initiators or a UV source. Further, there is no medicallysignificant release of heat during the cross-linking reaction. Moreover,a freeze-thaw process is not required, as is commonly used to formpoly(vinyl alcohol) hydrogels. Therefore, the nucleo-functional polymerand electro-functional polymer can be mixed easily in an operating room.Also, to the extent there are any unreacted nucleo-functional polymerand/or electro-functional polymer, the molecular weight of thesecomponents is desirably low enough that they will be readily clearedfrom the eye by natural processes.

Formation of a thiolated poly(vinyl alcohol) from PVA (in which some ofthe hydroxyl groups of the PVA remain esterified as acetate groups), andthen reaction of the thiolated poly(vinyl alcohol) with a poly(ethyleneglycol) containing thiol-reactive groups is illustrated in the schemebelow.

Refractive Index

The therapeutic methods and compositions can be characterized accordingto the refractive index of hydrogel formed. For example, in certainembodiments, the hydrogel has a refractive index in the range of fromabout 1.2 to about 1.5. In certain other embodiments, the hydrogel has arefractive index in the range of from about 1.3 to about 1.4. In certainother embodiments, the hydrogel has a refractive index in the range offrom about 1.30 to about 1.35, or from about 1.31 to about 1.36.

Transparency

The therapeutic methods and compositions can be characterized accordingto the transparency of the hydrogel formed. For example, in certainembodiments, the hydrogel has a transparency of at least 95% for lightin the visible spectrum when measured through hydrogel having athickness of 2 cm. In certain embodiments, the hydrogel has atransparency of at least 90%, 94%, or 98% for light in the visiblespectrum when measured through hydrogel having a thickness of 2 cm.

Density

The therapeutic methods and compositions can be characterized accordingto the density of the hydrogel formed. For example, in certainembodiments, the hydrogel has a density in the range of about 1 to about1.5 g/mL. In certain other embodiments, the hydrogel has a density inthe range of about 1 to about 1.2 g/mL, about 1.1 to about 1.3 g/mL,about 1.2 to about 1.3 g/mL, or about 1.3 to about 1.5 g/mL. In certainother embodiments, the hydrogel has a density in the range of about 1 toabout 1.2 g/mL. In certain other embodiments, the hydrogel has a densityin the range of about 1 to about 1.1 g/mL.

Gelation Time

The therapeutic methods and compositions can be characterized accordingto the gelation time of the hydrogel (i.e., how long it takes for thehydrogel to form once the nucleo-functional polymer has been combinedwith the electro-functional polymer). For example, in certainembodiments, the hydrogel has a gelation time from about 1 minute toabout 30 minutes after combining the nucleo-functional polymer and theelectro-functional polymer. In certain embodiments, the hydrogel has agelation time from about 5 minutes to about 30 minutes after combiningthe nucleo-functional polymer and the electro-functional polymer. Incertain other embodiments, the hydrogel has a gelation time from about 5minutes to about 20 minutes after combining the nucleo-functionalpolymer and the electro-functional polymer. In certain otherembodiments, the hydrogel has a gelation time from about 5 minutes toabout 10 minutes after combining the nucleo-functional polymer and theelectro-functional polymer. In certain other embodiments, the hydrogelhas a gelation time of less than about 1, 5, 10, 15, 20, 25, 30, 35, 40,45, 50, 55 or 60 minutes.

Elastic Modulus

The therapeutic methods and compositions can be characterized accordingto the elastic modulus of the hydrogel formed. For example, in certainembodiments, the hydrogel has an elastic modulus in the range of fromabout 200 Pa to about 15 kPa at a temperature of 25° C. In certainembodiments, the hydrogel has an elastic modulus in the range of fromabout 600 Pa to about 7 kPa at a temperature of 25° C.

Dynamic Viscosity

The therapeutic methods and compositions can be characterized accordingto the dynamic viscosity of the hydrogel formed. For example, in certainembodiments, the hydrogel has a dynamic viscosity in the range of about20 to 60 cP at a temperature of 20° C.

Biodegradation

The therapeutic methods and compositions can be characterized accordingwhether the hydrogel is biodegradable. Accordingly, in certainembodiments, the hydrogel is biodegradable. A biodegradable hydrogel canbe further characterized according to the rate at which the hydrogelundergoes biodegradation from the eye. In certain embodiments, thehydrogel undergoes complete biodegradation from the eye of the subjectwithin about 2 weeks to about 8 weeks. In certain embodiments, thehydrogel undergoes complete biodegradation from the eye of the subjectwithin about 3 weeks to about 5 weeks. In certain embodiments, thehydrogel undergoes complete biodegradation from the eye of the subjectwithin about 4 months to about 6 months. In certain embodiments, thehydrogel undergoes complete biodegradation from the eye of the subjectwithin about 3 days to about 7 days. In certain embodiments, thehydrogel undergoes complete biodegradation from the eye of the subjectwithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, or 24 weeks. In certain embodiments, the hydrogelundergoes complete biodegradation from the eye of the subject within 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, or 24 months.

In certain embodiments, the hydrogel has a biodegradation half-life inthe range of from about 4 days to about 20 days when disposed within thevitreous cavity of an eye. In certain embodiments, the hydrogel has abiodegradation half-life in the range of from about 1 month to about 2months when disposed within the vitreous cavity of an eye. In certainembodiments, the hydrogel has a biodegradation half-life in the range offrom about 1 week to about 3 weeks when disposed within the vitreouscavity of an eye. In certain embodiments, the hydrogel has abiodegradation half-life in the range of from about 8 weeks to about 15weeks when disposed within the vitreous cavity of an eye. In certainembodiments, the hydrogel has a biodegradation half-life of less than 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, or 24 weeks when disposed within the vitreous cavity of an eye.In certain embodiments, the hydrogel has a biodegradation half-life ofless than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, or 24 months when disposed within the vitreouscavity of an eye.

In yet other embodiments, the hydrogel turns into liquid afterapproximately 5 weeks at a temperature in the range of 20° C. to 25° C.,or within from about 4 weeks to 10 weeks, including all values andranges therein. In embodiments, the ester bonds remaining in thehydrogel may degrade at room temperature in solution, such as in aphosphate buffered saline solution. In embodiments, degradation maybegin after a few days and the hydrogel may be almost fully degraded,that is they form soluble products and the hydrogel turns in to liquidat around five weeks at a temperature in the range of 20° C. to 25° C.The rate of degradation will depend on a number of parameters, includingtotal crosslink density, number of ester linkages in the crosslinks andthe specifics of the environment.

Deliberate inclusion of degradable constituents into the nude-functionalpolymer and/or electro-functional polymer permits tuning of thedegradability and longevity of these materials in their chosenapplication. Examples of degradable constituents can be in thecrosslinks, or elsewhere and can include, for example, any molecule orgroup that contains an ester bond (e.g. carbamate, amide, carbonate,lactic acid, glycolic acid, caprolactone or others). In particularembodiments, the degradable elements may be incorporated at an amount inthe range of 1 to 6 per crosslinker. Similarly, incorporation of otherfunctional groups into the hydrogel, such as though modification of thepoly(vinyl alcohol) or poly(ethylene glycol) provide further degrees oftuning of the properties of the hydrogel.

Pressure Generated within the Eye

The therapeutic methods and compositions can be characterized accordingto the amount of pressured generated by the hydrogel in eye of thesubject. For example, in certain embodiments, the hydrogel generates apressure within the eye of less than 25 mmHg. In certain otherembodiments, the hydrogel generates a pressure within the eye in therange of from about 10 mmHg to about 25 mmHg. In certain otherembodiments, the hydrogel generates a pressure within the eye of about15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mmHg.

It is contemplated that upon initial formation of the hydrogel in theeye of a subject, the hydrogel will be in a hyperosmotic state, wherethe concentration of hydrogel is such that additional fluid is pulled in(if available) by the gel to swell it. This approach allows the injectedhydrogel to be filled passively to the size of the cavity, and then pullin additional water to exert an active swelling pressure on the interiorof the eye suitable for the tamponade affect. The extent of thehyperosmotic state would be tunable using the concentration of theactive ingredients. The source of the water in vivo would be the naturalaqueous production in the eye, which is known to be produced at a rateof approximately 2-3 μL/min.

Features of the Nucleo-Functional Polymer

The therapeutic methods and compositions for forming a hydrogel can becharacterized according to features of the nucleo-functional polymer.Accordingly, in certain embodiments, the nucleo-functional polymer is abiocompatible polymer selected from a polyalkylene andpolyheteroalkylene polymer each being substituted by (i) a plurality ofthio-functional groups —R¹—SH (where, as described above, R¹ is anester-containing linker), and optionally (ii) one or more hydroxyl,alkyl ester, hydroxyalkyl ester, or amide groups. In certainembodiments, the nucleo-functional polymer is a biocompatiblepolyalkylene polymer substituted by (i) a plurality of thio-functionalgroups —R¹—SH and (ii) a plurality of groups selected from the groupconsisting of hydroxyl, alkyl ester, hydroxyalkyl ester, and amide. Incertain embodiments, the nucleo-functional polymer is a biocompatiblepolymer selected from poly(vinyl alcohol), poly(vinyl alcoholmethacrylate), polyacrylamide, or poly(2-hydroxyethyl methacrylate),each being substituted by a plurality of thio-functional groups —R¹—SH.In certain embodiments, the nucleo-functional polymer is a biocompatiblepoly(vinyl alcohol) polymer substituted by a plurality ofthio-functional groups —R¹—SH. In certain embodiments, thenucleo-functional polymer is a biocompatible, partially hydrolyzedpoly(vinyl alcohol) polymer substituted by a plurality ofthio-functional groups —R¹—SH. In certain embodiments, thenucleo-functional polymer is a biocompatible, partially hydrolyzedpoly(vinyl alcohol) polymer substituted by a plurality ofthio-functional groups —R¹—SH, wherein the degree of hydrolysis of thepartially hydrolyzed poly(vinyl alcohol) polymer is at least 85%, 88%,90%, 92%, 95%, 97%, 98%, or 99%. In certain embodiments, thenucleo-functional polymer is a biocompatible, partially hydrolyzedpoly(vinyl alcohol) polymer substituted by a plurality ofthio-functional groups —R¹—SH, wherein the degree of hydrolysis of thepartially hydrolyzed poly(vinyl alcohol) polymer is at least 95%. Incertain embodiments, the nucleo-functional polymer is a biocompatible,partially hydrolyzed poly(vinyl alcohol) polymer substituted by aplurality of thio-functional groups —R¹—SH, wherein the degree ofhydrolysis of the partially hydrolyzed poly(vinyl alcohol) polymer is atleast 98%.

In certain embodiments, the thio-functional group —R¹—SH is—OC(O)—(C₁-C₆ alkylene)-SH. In certain embodiments, the thio-functionalgroup —R¹—SH is —OC(O)—(CH₂CH₂)—SH.

As described in the literature, poly(vinyl alcohol) is prepared by firstpolymerizing vinyl acetate to produce poly(vinyl acetate), and then thepoly(vinyl acetate) is subjected to hydrolytic conditions to cleave theester bond of the acetate group leaving only a hydroxyl group bound tothe polymer backbone. Depending on the hydrolytic conditions used tocleave the ester bond of the acetate group, the resulting polymerproduct may still contain some acetate groups. That is, not all theacetate groups on the polymer are cleaved. For this reason, per commonnomenclature used in the literature, the poly(vinyl alcohol) can befurther characterized according to whether it is (a) fully hydrolyzed(i.e., all the acetate groups from the starting poly(vinyl acetate)starting material that have been converted to hydroxyl groups)) or (b)partially hydrolyzed (i.e., where some percentage of acetate groups fromthe poly(vinyl acetate) starting material have not been converted tohydroxyl groups). A partially hydrolyzed poly(vinyl alcohol) can bereferred to as a poly(vinyl alcohol-covinyl acetate)). Per common usagein the literature, a poly(vinyl alcohol) that is partially hydrolyzedcan be characterized according to the degree of hydrolysis (i.e., thepercentage of acetate groups from the starting poly(vinyl acetate)starting material that have been converted to hydroxyl groups), such asgreater than about 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Incertain embodiments, the degree of hydrolysis is in the range of fromabout 75% to about 95%, about 80% to about 95%, about 80% to about 90%,about 80% to about 85%, about 85% to about 95%, or about 85% to about90%. For clarity, the term “poly(vinyl alcohol)” used herein encompassesboth (a) fully hydrolyzed (i.e., all the acetate groups from thestarting poly(vinyl acetate) starting material have been converted tohydroxyl groups)) and (b) partially hydrolyzed (i.e., where somepercentage of acetate groups from the poly(vinyl acetate) startingmaterial have not been converted to hydroxyl groups) material.

In certain embodiments, the nucleo-functional polymer is a biocompatiblepoly(vinyl alcohol) polymer comprising:

wherein a is an integer from 1-20 and b is an integer from 1-20.

In certain embodiments, the nucleo-functional polymer is a biocompatiblepoly(vinyl alcohol) polymer comprising:

wherein a is an integer from 1-20, b is an integer from 1-20, and c isan integer from about 20 to about 500.

The nucleo-functional polymer may be further characterized according toits molecular weight, such as the weight-average molecular weight of thepolymer. In certain embodiments, the nucleo-functional polymer has aweight-average molecular weight in the range of from about 500 g/mol toabout 1,000,000 g/mol. In certain embodiments, the nucleo-functionalpolymer has a weight-average molecular weight in the range of from about2,000 g/mol to about 500,000 g/mol. In certain embodiments, thenucleo-functional polymer has a weight-average molecular weight in therange of from about 4,000 g/mol to about 30,000 g/mol. In certainembodiments, the nucleo-functional polymer has a weight-averagemolecular weight less than about 200,000 g/mol or less than about100,000 g/mol. In certain embodiments, the nucleo-functional polymer hasa weight-average molecular weight in the range of from about 26,000g/mol to about 32,000 g/mol. In certain embodiments, thenucleo-functional polymer has a weight-average molecular weight of about29,000 g/mol. In certain embodiments, the nucleo-functional polymer hasa weight-average molecular weight of about 30,000 g/mol. In certainembodiments, the nucleo-functional polymer has a weight-averagemolecular weight in the range of from about 45,000 g/mol to about 55,000g/mol. In certain embodiments, the nucleo-functional polymer has aweight-average molecular weight of about 50,000 g/mol.

In a more specific embodiment, the nucleo-functional polymer is athiolated poly(vinyl alcohol) that has been fully hydrolyzed orpartially hydrolyzed (e.g., hydrolysis of about 75% or more, includingall values and ranges from 75% to 99.9%, including 75%, 80%, 85%, 90%,95%, 96%, 97%, 98%, 99%, etc.). The thiolated poly(vinyl alcohol) may befurther characterized according to its molecular weight, such as wherethe thiolated poly(vinyl alcohol) has a weight average molecular weight(Mw) the range of 2 kDa to 2,000,000 kDa, including all values andranges therein, and such as 2 kDa to 1,000,000 kDa, 2 kDa to 200 kDa,and 30 kDa to 50 kDa, etc. The thiolated poly(vinyl alcohol) may beprovided in a solution, dissolved in water or other solvents (including,but not limited to, dimethyl sulfoxide (DMSO) or dimethylformamide(DMF)) at any viable concentration and preferably at a concentration inthe range of 0.0001 wt % to 50 wt %, including all values and incrementstherein.

The thiolated poly(vinyl alcohol) can be prepared by reacting a range ofthiol containing functional groups with poly(vinyl alcohol), as furtherdescribed in U.S. Patent Application Publication No. 2016/0009872, whichis hereby incorporated by reference. In certain embodiments, thiolatedpoly(vinyl alcohol) is prepared by reacting (a) a compound having athiol functionality and at least one hydroxyl-reactive group, such as,for example, a carboxyl group, represented by HS—R—CO₂H, where R mayinclude an alkane, unsaturated ether, or ester group, and R includesfrom 1 to 20 carbons, with (b) a poly(vinyl alcohol).

In other more specific embodiments, the thiolated poly(vinyl alcohol)comprises the following fragment:

wherein R includes 1 to 20 carbons and may be an alkane, saturated etheror ester, and the individual units are randomly distributed along thelength of the poly(vinyl alcohol) chain. X is in the range of 0.1-10%, nis in the range of 80-99.9%, indicating the level of hydrolysis of thepoly(vinyl alcohol) polymer and allowing for water solubility of thepolymer and m, the amount of non-hydrolyzed acetate groups, is in therange 0.1-20%.

The amount of thiol groups on the poly(vinyl alcohol) can be controlledby the number of hydroxyl groups on the poly(vinyl alcohol) that undergoreaction with the thiolating agent to generate the thiolated poly(vinylalcohol). In certain embodiments, the amount of thiol functional groupson the poly(vinyl alcohol) may be characterized according to the molarratio of thiol functional groups to poly(vinyl alcohol) polymer, such asfrom about 0.1:1 to about 10.0:1, including all values and rangestherein. Furthermore, the amount of thiol groups on the poly(vinylalcohol) can be regulated by the reaction temperature and reaction timeused when reacting the thiolating agent with the poly(vinyl alcohol) toform the thiolated poly(vinyl alcohol). In certain embodiments, thereaction temperature may be in the range of 40° C. to 95° C., andreaction time may be in the range of 5 hours to 48 hours, including allvalues and ranges therein. Of course, cooler reaction temperatures maybe utilized as well, such as in the range of 20° C. up to 40° C.

More generally, the nucleo-functional polymer containing a plurality ofthio-functional groups can be prepared based on procedures described inthe literature, such as U.S. Patent Application 2016/0009872 in which apolymer having nucleophilic groups (e.g., hydroxyl groups) is reactedwith a thiol-containing compound so that resulting polymer contains athiol group bound to the polymer backbone via a linker.

Features of the Electro-Functional Polymer

The therapeutic methods and compositions for forming a hydrogel can becharacterized according to features of the electro-functional polymer.Accordingly, in certain embodiments, the electro-functional polymer is abiocompatible polymer selected from a polyalkylene andpolyheteroalkylene polymer each being substituted by at least onethiol-reactive group. In certain embodiments, the electro-functionalpolymer is a biocompatible polyheteroalkylene polymer substituted by atleast one thiol-reactive group. In certain embodiments, theelectro-functional polymer is a biocompatible poly(oxyalkylene) polymersubstituted by at least one thiol-reactive group. In certainembodiments, the electro-functional polymer is a biocompatiblepoly(ethyleneglycol) polymer substituted by at least one thiol-reactivegroup.

In certain embodiments, the thiol-reactive group is an alpha-betaunsaturated ester, maleimidyl, or

each of which is optionally substituted by one or more occurrences ofalkyl, aryl, or aralkyl. In certain embodiments, the thiol-reactivegroup is an alpha-beta unsaturated ester optionally substituted by oneor more occurrences of alkyl, aryl, or aralkyl. In certain embodiments,the thiol-reactive group is —OC(O)CH═CH₂.

In certain embodiments, the electro-functional polymer has the formula:

wherein R* is independently for each occurrence hydrogen, alkyl, aryl,or aralkyl; and m is an integer in the range of 5 to 15,000. In certainembodiments, R* is hydrogen. In yet other embodiments, m is an integerin the range of from about 20 to about 100, about 100 to about 500,about 500 to about 750, about 750 to about 1,000, about 1,000 to about2,000, about 2,000 to about 5,000, about 5,000 to about 7,500, about7,500 to about 10,000, about 10,000 to about 12,500, about 12,500 toabout 15,000.

The electro-functional polymer may be further characterized according toits molecular weight, such the weight-average molecular weight of thepolymer. Accordingly, in certain embodiments, the electro-functionalpolymer has a weight-average molecular weight in the range of from about500 g/mol to about 1,000,000 g/mol. In certain embodiments, theelectro-functional polymer has a weight-average molecular weight in therange of from about 1,000 g/mol to about 100,000 g/mol. In certainembodiments, the electro-functional polymer has a weight-averagemolecular weight in the range of from about 2,000 g/mol to about 8,000g/mol. In certain embodiments, the electro-functional polymer has aweight-average molecular weight less than about 200,000 g/mol or lessthan about 100,000 g/mol. In certain embodiments, the electro-functionalpolymer has a weight-average molecular weight in the range of from about3,000 g/mol to about 4,000 g/mol. In certain embodiments, theelectro-functional polymer has a weight-average molecular weight in therange of from about 3,200 g/mol to about 3,800 g/mol. In certainembodiments, the electro-functional polymer has a weight-averagemolecular weight of about 3,500 g/mol.

The electro-functional polymer may be a straight-chain polymer or abranched chain polymer. In yet other embodiments, the electro-functionalpolymer may be a multi-arm polymer described in U.S. Pat. No. 9,072,809,which is hereby incorporated by reference, such as pentaerythritolpolyethylene glycol maleimide (4ARM-PEG-MAL) (molecular weight selectedfrom about 5,000 to about 40,000, e.g., 10,000 or 20,000),pentaerythritol polyethylene glycol succinimidyl succinate (4ARM-PEG-SS)(molecular weight selected from about 5,000 to about 40,000, e.g.,10,000 or 20,000), pentaerythritol polyethylene glycol succinimidylglutarate (4ARMPEG-SG) (molecular weight selected from about 5,000 toabout 40,000, e.g., 10,000 or 20,000), pentaerythritol polyethyleneglycol succinimidyl glutaramide (4ARM-PEG-SGA) (molecular weightselected from about 5,000 to about 40,000, e.g., 10,000 or 20,000),hexaglycerin polyethylene glycol succinimidyl succinate (8ARM-PEG-SS)(molecular weight selected from about 5,000 to about 40,000, e.g.,10,000 or 20,000), hexaglycerin polyethylene glycol succinimidylglutarate (8ARM-PEG-SG) (molecular weight selected from about 5,000 toabout 40,000, e.g., 10,000, 15,000, 20,000, or 40,000), hexaglycerinpolyethylene glycol succinimidyl glutaramide (8ARM-PEG-SGA) (molecularweight selected from about 5,000 to about 40,000, e.g., 10,000, 15,000,20,000, or 40,000), tripentaerythritol polyethylene glycol succinimidylsuccinate (8ARM(TP)-PEG-SS) (molecular weight selected from about 5,000to about 40,000, e.g., 10,000 or 20,000), tripentaerythritolpolyethylene glycol succinimidyl glutarate (8ARM(TP)-PEG-SG) (molecularweight selected from about 5,000 to about 40,000, e.g., 10,000, 15,000,20,000, or 40,000), or tripentaerythritol polyethylene glycolsuccinimidyl glutaramide (8ARM(TP)-PEG-SGA) (molecular weight selectedfrom about 5,000 to about 40,000, e.g., 10,000, 15,000, 20,000, or40,000).

In another more specific embodiment, the electro-functional polymer maybe a poly(ethylene glycol) end-capped with at least two thiol-reactivegroups. The poly(ethylene glycol) may be linear, branched, a dendrimer,or multi-armed. The thiol reactive group may be, for example, anacrylate, methacrylate, maleimidyl, haloacetyl, pyridyldithiol, orN-hydroxysuccinimidyl. An exemplary poly(ethylene glycol) end-cappedwith thiol-reactive groups may be represented by the formulaY—[—O—CH₂CH₂-]_(n)-O—Y wherein each Y is a thiol-reactive group, and nis, for example, in the range of 200 to 20,000. In another more specificembodiment, the electro-functional polymer may beCH₂═CHC(O)O—[—CH₂CH₂—O-]_(b)-C(O)CH═CH₂, wherein b is, for example, inthe range of about 200 to about 20,000. Alternatively or additionally tothe linear embodiments depicted above, the poly(ethylene glycol) may bea dendrimer. For example, the poly(ethylene glycol) may be a 4 to 32hydroxyl dendron. In further embodiments, the poly(ethylene glycol) maybe multi-armed. In such embodiments, the poly(ethylene glycol) may be,for example, a 4, 6 or 8 arm and hydroxy-terminated. The molecularweight of the poly(ethylene glycol) may be varied, and in some cases oneof the thiol-reactive groups may be replaced with other structures toform dangling chains, rather than crosslinks. In certain embodiments,the molecular weight (Mw) is less than 20,000, including all values andranges from 200 to 20,000, such as 200 to 1,000, 1,000 to 10,000, etc.In addition, the degree of functionality may be varied, meaning that thepoly(ethylene glycol) may be mono-functional, di-functional ormulti-functional.

More generally, the electro-functional polymer can be purchased fromcommercial sources or prepared based on procedures described in theliterature, such as by treating a nucleo-functional polymer withreagent(s) to install one or more electrophilic groups (e.g., byreacting polyethylene glycol with acrylic acid in an esterificationreaction to form polyethylene glycol diacrylate).

Relative Amount of Nucleo-Functional Polymer and Electro-FunctionalPolymer

The therapeutic methods and compositions for forming a hydrogel can becharacterized according to relative amount of nucleo-functional polymerand electro-functional polymer used. Accordingly, in certainembodiments, the mole ratio of (i) thio-functional groups —R¹—SH to (ii)thiol-reactive group is in the range of 10:1 to 1:10. In certainembodiments, the mole ratio of (i) thio-functional groups —R¹—SH to (ii)thiol-reactive groups is in the range of 5:1 to 1:1. In certainembodiments, the mole ratio of (i) thio-functional groups —R¹—SH to (ii)thiol-reactive groups is in the range of 2:1 to 1:1.

In a more specific embodiment, a thiolated poly (vinyl alcohol) andpoly(ethylene glycol)-diacrylate are delivered at a ratio of functionalgroups (mmol/mmol) in the range of 2:1 to 0.5:1, including all valuesand ranges therein, and preferably 1:1. Furthermore, once combined thecombination of the thiolated poly(vinyl alcohol) and the poly(ethyleneglycol)-diacrylate are present in solution in the range of about 6 mg/mLto about 250 mg/mL, including all values and ranges therein, andpreferably about 25 mg/mL to about 65 mg/mL, and sometimes about 45mg/mL. The viscosity of the thiolated poly(vinyl alcohol) and thepoly(ethylene glycol)-diacrylate, prior to crosslinking and gelation, isin the range of about 0.005 Pa*s to about 0.35 Pa*s, including allvalues and ranges therein, such as in the range of about 0.010 Pa*s toabout 0.040 Pa*s, and sometimes about 0.028 Pa*s.

Administration Features of Nucleo-Functional Polymer andElectro-Functional Polymer

The method may be further characterized according to whether thenucleo-functional polymer and the electro-functional polymer areadministered together as a single composition to the vitreous cavity ofthe eye of the subject, or alternatively the nucleo-functional polymerand the electro-functional polymer are administered separately to thevitreous cavity of the eye of the subject. In certain embodiments, thenucleo-functional polymer and the electro-functional polymer areadministered together as a single composition to the vitreous cavity ofthe eye of the subject. The single composition may further comprise, forexample, a liquid pharmaceutically acceptable carrier for administrationto the eye of a subject. In certain embodiments, the nucleo-functionalpolymer and the electro-functional polymer are administered together asa single, liquid aqueous pharmaceutical composition to the vitreouscavity of the eye of the subject.

In certain other embodiments, the nucleo-functional polymer and theelectro-functional polymer are administered separately to the vitreouscavity of the eye of the subject. Even when administered separately, thenucleo-functional polymer may be administered as a liquid ocularformulation comprising a liquid pharmaceutically acceptable carrier foradministration to the eye of a subject. This facilitates easyadministration of the nucleo-functional polymer through surgical portsin the eye of the subject. Similarly, the electro-functional polymer maybe administered as a liquid ocular formulation comprising a liquidpharmaceutically acceptable carrier for administration to the eye of asubject. This facilitates easy administration of the electro-functionalpolymer through surgical ports in the eye of the subject. Accordingly,in certain embodiments, the nucleo-functional polymer and theelectro-functional polymer are administered separately to the vitreouscavity of the eye of the subject, wherein the nucleo-functional polymeris administered as a single, liquid aqueous pharmaceutical compositionto the vitreous cavity of the eye of the subject, and theelectro-functional polymer is administered as a single, liquid aqueouspharmaceutical composition to the vitreous cavity of the eye of thesubject.

The liquid aqueous pharmaceutical composition may be furthercharacterized according to, for example, pH, osmolality and presenceand/or identity of salts. In certain embodiments, the liquid aqueouspharmaceutical composition has a pH in the range of about 7.1 to about7.7. In certain embodiments, the liquid aqueous pharmaceuticalcomposition has a pH in the range of about 7.3 to about 7.5. In certainembodiments, the liquid aqueous pharmaceutical composition has a pH ofabout 7.4. In certain embodiments, the liquid aqueous pharmaceuticalcomposition further comprises an alkali metal salt. In certainembodiments, the liquid aqueous pharmaceutical composition furthercomprises an alkali metal halide salt, an alkaline earth metal halidesalt, or a combination thereof. In certain embodiments, the liquidaqueous pharmaceutical composition further comprises sodium chloride. Incertain embodiments, the liquid aqueous pharmaceutical compositionfurther comprises sodium chloride, potassium chloride, calcium chloride,magnesium chloride, or a combination of two or more of the foregoing. Incertain embodiments, the liquid aqueous pharmaceutical composition hasan osmolality in the range of about 280 mOsm/kg to about 315 mOsm/kg. Incertain embodiments, the liquid aqueous pharmaceutical composition hasan osmolality in the range of about 280 mOsm/kg to about 300 mOsm/kg. Incertain embodiments, the liquid aqueous pharmaceutical composition hasan osmolality in the range of about 285 mOsm/kg to about 295 mOsm/kg. Incertain embodiments, the liquid aqueous pharmaceutical composition hasan osmolality of about 290 mOsm/kg.

A liquid formulation containing (i) a nucleo-functional polymer and/orthe electro-functional polymer and (ii) a liquid pharmaceuticallyacceptable carrier for administration to the eye of a subject may befurther characterized according to the viscosity of the formulation. Incertain embodiments, the liquid formulation has a viscosity within 10%,25%, 50%, 75%, 100%, 150%, 200%, or 300% of water. In certain otherembodiments, the liquid formulation has a viscosity such that it can beadministered through a needle having a gauge of less than or equal to 23using a force of no more than 5N. In certain embodiments, the liquidformulation has a viscosity such that 1-2 mL of the liquid formulationcan be administered within 3 minutes using a needle having a gauge ofless than or equal to 23 using a force of no more than 5N.

In a more specific embodiment, a nucleo-functional polymer and/or theelectro-functional polymer are provided in an aqueous pharmaceuticalcomposition for administration to the eye. Such aqueous pharmaceuticalcompositions are desirably low viscosity liquids. In embodiments, theliquids exhibit a viscosity in the range of 0.004 Pa*s to 0.5 Pa*s,including all values and ranges therein, such as 0.010 Pa*s to 0.05Pa*s. For example, an aqueous pharmaceutical composition may desirablycomprise poly(ethylene glycol) diacrylate at a concentration of 3 mg/mLto 300 mg/mL, including all values and ranges therein, such as in therange of 10 mg/mL to 50 mg/mL, and even the more specific value of about30 mg/mL. Another more specific embodiment is a poly(ethylene glycol)diacrylate aqueous solution having a viscosity in the range of 0.007Pa*s to 0.5 Pa*s, including all values and ranges therein, such as inthe range of 0.01 Pa*s to 0.05 Pa*s, or the more specific value of about0.035 Pa*s. Another more specific embodiment is a thiolated poly(vinylalcohol) aqueous solution containing the thiolated poly(vinyl alcohol)at a range of 10 mg/mL to 200 mg/mL, including all values and rangestherein, such as the range of 40 mg/mL to 80 mg/mL, and the morespecific value of about 60 mg/mL. Another more specific embodiment isthiolated poly(vinyl alcohol) aqueous solution having a viscosity in therange of 0.004 Pa*s to 0.2 Pa*s, including all values and rangestherein, such as in the range of 0.010 Pa*s to 0.040 Pa*s, or the morespecific value of about 0.020 Pa*s.

It is appreciated that the properties and gelation times of the in situformed gels can be regulated by the concentration of thiolatedpoly(vinyl alcohol) and poly(ethylene glycol)-diacrylate, their ratioused for cross-linking and functionality (amount of thiol groups linkedto poly(vinyl alcohol) and the amount of thiol reactive groups perpoly(ethylene glycol) molecule). By changing the thiolated poly(vinylalcohol) to poly(ethylene glycol) ratio, one can also regulate thefraction of dangling poly(ethylene glycol) chains that can be used toimprove hydrogel's surface properties. Furthermore, mixing a blend ofmono-functional and bi-functional poly(ethylene glycol) crosslinkers,wherein the functionality is the thiol reactive groups will allow thetuning of the crosslinking versus hydrophilicity of the hydrogel.Control of the length of the mono-functional and bi-functionalcrosslinker or the size of the starting poly(vinyl alcohol), allowsmodification of mechanical properties, swelling, lubricity, morphology,and hydrophilicity as well as frictional and wear properties. Thesefeatures described in connection with thiolated poly(vinyl alcohol) andpoly(ethylene glycol)-diacrylate apply generally for the broader scopeof nucleo-functional polymers and electro-functional polymers describedherein.

Additional Step of Removing Vitreous Humor from the Eye

The method may optionally further comprise the step of removing vitreoushumor from the eye prior to administration of the nucleo-functionalpolymer and the electro-functional polymer.

III. Injectable Ocular Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising (i) anucleo-functional polymer and/or an electro-functional polymer and (ii)a pharmaceutically acceptable carrier for administration to the eye.Preferably, the pharmaceutical composition is a liquid pharmaceuticalcomposition. The pharmaceutically acceptable carrier may be water or anyother liquid suitable for administration to the eye of a subject.

The pharmaceutical composition is sterile and may optionally contain apreservative, antioxidant, and/or viscosity modifier. Exemplaryviscosity modifiers include, for example, acacia, agar, alginic acid,bentonite, carbomers, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carrageenan, ceratonia, cetostearylalcohol, chitosan, colloidal silicon dioxide, cyclomethicone,ethylcellulose, gelatin, glycerin, glyceryl behenate, guar gum,hectorite, hydrogenated vegetable oil type I, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylstarch, hypromellose, magnesium aluminum silicate, maltodextrin,methylcellulose, polydextrose, polyethylene glycol, poly(methylvinylether/maleic anhydride), polyvinyl acetate phthalate, polyvinyl alcohol,potassium chloride, povidone, propylene glycol alginate, saponite,sodium alginate, sodium chloride, stearyl alcohol, sucrose,sulfobutylether (3-cyclodextrin), tragacanth, xanthan gum, andderivatives and mixtures thereof. In some embodiments, the viscositymodifier is a bioadhesive or comprises a bioadhesive polymer.

In some embodiments, the concentration of the viscosity modifier in thepharmaceutical composition ranges from 0.1 to 20% by weight. In certainembodiments, the concentration of the viscosity modifier in thepharmaceutical composition ranges from 5 to 20% by weight. In certainembodiments, the concentration of the viscosity modifier in thepharmaceutical composition is less than 20%, less than 15%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, less than 1.8%, less than1.6%, less than 1.5%, less than 1.4%, less than 1.2%, less than 1%, lessthan 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1%by weight.

The pharmaceutical composition may be further characterized according toits viscosity. In certain embodiments, the viscosity of thepharmaceutical composition is less than 4000 cP, less than 2000 cP, lessthan 1000 cP, less than 800 cP, less than 600 cP, less than 500 cP, lessthan 400 cP, less than 200 cP, less than 100 cP, less than 80 cP, lessthan 60 cP, less than 50 cP, less than 40 cP, less than 20 cP, less than10 cP, less than 8 cP, less than 6 cP, less than 5 cP, less than 4 cP,less than 3 cP, less than 2 cP, less than 1 cP. In some embodiments, theviscosity of the pharmaceutical composition is at least 4,000 cP, atleast 2,000 cP, at least 1,000 cP, at least 800 cP, at least 600 cP, atleast 500 cP, at least 400 cP, at least 200 cP, at least 100 cP, atleast 80 cP, at least 60 cP, at least 50 cP, at least 40 cP, at least 20cP, at least 10 cP, at least 8 cP, at least 6 cP, at least 5 cP, atleast 4 cP, at least 3 cP, at least 2 cP, at least 1 cP. In certainembodiments, the viscosity of the pharmaceutical composition is about4,000 cP, about 2,000 cP, about 1,000 cP, about 800 cP, about 600 cP,about 500 cP, about 400 cP, about 200 cP, about 100 cP, about 80 cP,about 60 cP, about 50 cP, about 40 cP, about 20 cP, about 10 cP, about 8cP, about 6 cP, about 5 cP, about 4 cP, about 3 cP, about 2 cP, about 1cP. In some embodiments, the viscosity of the viscosity of thepharmaceutical composition is between about 5 cP and 50 cP.

The pharmaceutical composition may be further characterized according toits pH. In certain embodiments, the pharmaceutical composition has a pHin the range of from about 5 to about 9, or about 6 to about 8. Incertain embodiments, the pharmaceutical composition has a pH in therange of from about 6.5 to about 7.5. In certain embodiments, thepharmaceutical composition has a pH of about 7.

In certain embodiments, the pharmaceutical composition contains water,and the formulation has a pH in the range of about 7.1 to about 7.7. Incertain embodiments, the pharmaceutical composition contains water, andthe formulation has a pH in the range of about 7.1 to about 7.6, about7.1 to about 7.5, about 7.1 to about 7.4, about 7.2 to about 7.6, about7.2 to about 7.5, about 7.2 to about 7.4, about 7.2 to about 7.3, about7.3 to about 7.7, about 7.3 to about 7.6, about 7.3 to about 7.5, about7.3 to about 7.4, about 7.4 to about 7.7, about 7.4 to about 7.6, orabout 7.4 to about 7.5. In certain embodiments, the pharmaceuticalcomposition contains water, and the formulation has a pH in the range ofabout 7.3 to about 7.5. In certain embodiments, the pharmaceuticalcomposition contains water, and the formulation has a pH of about 7.4.

The pharmaceutical composition may be further characterized according toosmolality and the presence and/or identity of salts. For example, incertain embodiments, the pharmaceutical composition has an osmolality inthe range of about 280 mOsm/kg to about 315 mOsm/kg. In certainembodiments, the pharmaceutical composition has an osmolality in therange of about 280 mOsm/kg to about 300 mOsm/kg. In certain embodiments,the pharmaceutical composition has an osmolality in the range of about285 mOsm/kg to about 295 mOsm/kg. In certain embodiments, thepharmaceutical composition has an osmolality of about 290 mOsm/kg. Incertain embodiments, the pharmaceutical composition further comprises analkali metal salt. In certain embodiments, the pharmaceuticalcomposition further comprises an alkali metal halide salt, an alkalineearth metal halide salt, or a combination thereof. In certainembodiments, the pharmaceutical composition further comprises sodiumchloride. In certain embodiments, the pharmaceutical composition furthercomprises sodium chloride, potassium chloride, calcium chloride,magnesium chloride, or a combination of two or more of the foregoing.

IV. Kits for Use in Medical Applications

Another aspect of the invention provides a kit for treating a disorder.The kit comprises: i) instructions for achieving one of the methodsdescribed herein (e.g., method for contacting retinal tissue in the eyeof a subject with a hydrogel, methods for supporting retinal tissue, andmethods for treating a subject with a retinal detachment); and ii) annucleo-functional polymer described herein and/or an electro-functionalpolymer described herein.

The description above describes multiple aspects and embodiments of theinvention. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1—Preparation and Characterization of an Exemplary Hydrogel

Hydrogel is formed by reaction of a thiolated poly(vinyl alcohol)(abbreviated TPVA) with a poly(ethylene glycol) diacrylate (abbreviatedPEGDA). TPVA is prepared by an esterification reaction of PVA with3-mercaptopropionic acid and characterized by ¹H NMR. The formed TPVAcontains pendant chains with ester bonds linking the thiol groups to thePVA backbone. The gelation reaction between TPVA and PEGDA proceeds atphysiological conditions in an aqueous environment without radicalinitiators or irradiation.

Hydrogel Formation

Gelation time and elastic modulus (G′) values for exemplary hydrogelsare provided in Table 1. Rapid gelation time is important because agelation time of several hours for cross-linking creates the risk ofadverse medical events, such as sub-retinal migration which would beclinically catastrophic and lead to re-detachment.

TABLE 1 Gelation time and modulus for preliminary formulation Polymer25° C. 37° C. conc, % Gel time Get time [w/v] [min] G’ [Pa] G” [Pa][min] G’ [Pa] G” [Pa] 3.0 23.3 803 5 4.2 3607 460 4.5 92 6440 133 3.09660 260Hydrogel Degradation

Degradation of the hydrogel is facilitated by the presence of estergroups in the hydrogel, which are easily hydrolysable and do not requirethe presence of enzymes for degradation to occur. The degradability andswellability of exemplary PVA-PEG hydrogels have been tested in 1×PBS atambient temperature. Hydrogels at 3 wt % polymer solids starteddisintegrating after 18 days and completely solubilized after 35 days,as described in U.S. Patent Application Publication US 2016/0009872.

GPC has been used to analyze the initial products of the in vitrodegradation process. A GPC chromatogram is provided in FIG. 1 , which islabeled according to identified materials which include TPVA, PEGDA, andTVPA/PEGDA degradation products.

Example 2—Preparation and Characterization of Additional ExemplaryHydrogel

A hydrogel was formed by reaction of a thiolated poly(vinyl alcohol)(abbreviated TPVA) with a poly(ethylene glycol) diacrylate (abbreviatedPEGDA). Physical properties of the hydrogel were analyzed, as describedbelow.

Hydrogel Formation

To a polypropylene disposable cuvette was added 1 mL of a TPVA solutionand 1 mL of a PEGDA solution, to thereby form a hydrogel premix. Thehydrogel premix was placed in a static incubator at a temperature of 37°C. for approximately 8 minutes during which time gelation occurred, tothereby provide the test hydrogel.

The TPVA solution was 6% w/w thiolated poly(vinyl alcohol) in phosphatebuffered saline. The thiolated poly(vinyl alcohol) polymer is apoly(vinyl alcohol) in which approximately 4.3% of the hydroxyl groupson the polymer have been replaced with —OC(O)CH₂CH₂—SH. A ¹H NMR (D₂O)spectrum of the thiolated poly(vinyl alcohol) polymer is shown in FIG. 2, which as illustrated has a peak at 2.697 ppm (corresponding to twohydrogen atoms, which are believed to be due to the CH₂ group attachedto the —SH group) and a peak at 3.889 ppm (corresponding to one hydrogenatom, which is believed to be due to the C—H hydrogen atom on thepolymer backbone for carbon atoms bearing a hydroxyl group). Theweight-average molecular weight of the thiolated poly(vinyl alcohol)polymer was calculated to be about 29,000 g/mol. The thiolatedpoly(vinyl alcohol) polymer was prepared from poly(vinyl alcohol) havinga weight-average molecular weight of approximately 27,000 g/mol, basedon procedures described in Ossipov et al. in Macromolecules (2008), vol.41(11), pages 3971-3982.

The PEGDA solution is 3% w/w poly(ethylene glycol) diacrylate inphosphate buffered saline, wherein the poly(ethylene glycol) diacrylatehas a weight average molecular weight of approximately 3,400 g/mol.

Analysis of UV-Visible Light Absorbance

UV-Visible light absorbance of the test hydrogel was analyzed by placingthe test hydrogel in a Thermo Scientific Genesys 10S UV-Visspectrophotometer and performing an absorbance scan across wavelengthsranging from 300 nm to 900 nm. Absorbance values for the test hydrogelwere analyzed relative to absorbance values obtained using a blankcuvette containing distilled water. Results of the UV-Visible lightabsorbance scan of the test hydrogel are shown in FIG. 3 .

Example 3—Refractive Index of Exemplary Hydrogel

An aliquot of the TPVA solution from Example 2 was mixed with an equalvolume of an aliquot of the PEGDA solution from Example 2 to produce ahydrogel premix, and a 1 mL aliquot of the hydrogel premix was placed ina refractive index detector at a temperature of 37° C. The hydrogel wasallowed to form. Once the hydrogel had formed, the refractive index ofthe hydrogel was measured and determined to be 1.3376. The instrumentused to measure the refractive index was an Anton Paar Abbemat 200Refractometer.

Example 4—Gelation Time and Elastic Modulus for Exemplary Hydrogel

A 1 mL aliquot of the TPVA solution from Example 2 was mixed with a 1 mLaliquot of the PEGDA solution from Example 2, and the resulting mixturewas placed onto the top platform of TA brand Advanced Rheometer AR 550.The top platform was maintained at a temperature of 37° C. A 60 mm 2°cone was applied to the mixture to provide the top geometry. Rheologicalproperties of the mixture on the top platform were measured over aperiod of 30 minutes with oscillation at predetermined time points at aspeed of 6.283 rad/s. Results are shown in FIG. 4 .

Example 5—Transmission of Hydrogel Premix Through Surgical Port

An aliquot of the TPVA solution from Example 2 was mixed with an equalvolume of an aliquot of the PEGDA solution from Example 2 to produce ahydrogel premix. The premix was immediately loaded into a syringe havingan injection needle with an inside diameter of approximately 300micrometers. The premix was easily dispensed from the syringe throughthe injection needle. FIG. 5 is an illustration of hydrogel premix thathas been dispensed from the syringe into a container. Once the hydrogelpremix had been dispensed into the container, the hydrogel premix wasobserved to form a hydrogel in approximately 3-5 minutes at atemperature of approximately 37° C. FIG. 6 is an illustration of thehydrogel that formed in the container, where the container is held in avertical position.

Example 6—In Vitro Toxicity Analysis for Exemplary Hydrogel

An aliquot of the TPVA solution described in Example 2 was mixed with anequal volume of an aliquot of a PEGDA solution described in Example 2 toproduce a hydrogel premix contained in a 15 mL tube, noting that in thisexperiment (i) the thiolated poly(vinyl alcohol) was treated withultra-violet light (254 nm) for a few minutes before mixing withphosphate buffered saline to form the TPVA solution, and (ii) thepoly(ethylene glycol) diacrylate was treated with ultra-violet light(254 nm) for a few minutes before mixing with phosphate buffered salineto form the PEGDA solution. The hydrogel premix was allowed to gel for aduration of 20 minutes at a temperature of 37° C., in order to form thehydrogel.

Samples of the (i) thiolated poly(vinyl alcohol), (ii) poly(ethyleneglycol) diacrylate, and (iii) hydrogel were subjected to in vitrotoxicity analysis according to an ISO 10993-5 cytotoxicity protocolperformed by Nelson Laboratories.

To test the in vitro toxicity of thiolated poly(vinyl alcohol), analiquot of thiolated poly(vinyl alcohol) was mixed withserum-supplemented mammalian cell culture media (MEM) to generate amixture that was 6% w/w thiolated poly(vinyl alcohol). The resultingmixture was applied to L929 cells. The cells were evaluated for evidenceof toxicity effects due to the mixture. Results of the assay were that ascore of 1 was observed indicating “slight cytotoxicity.”

To test the in vitro toxicity of poly(ethylene glycol) diacrylate, analiquot of poly(ethylene glycol) diacrylate was mixed with MEM togenerate a mixture that was 3% w/w poly(ethylene glycol) diacrylate. Theresulting mixture was applied to L929 cells. The cells were evaluatedfor evidence of toxicity effects due to the mixture. Results of theassay were that a score of 1 was observed indicating “slightcytotoxicity.”

To test the in vitro toxicity of the hydrogel, the hydrogel wasextracted with MEM, and the resulting extract was applied to L929 cells.The cells were evaluated for evidence of toxicity effects due to theextract. Results of the assay were that a score of 0 was observedindicating “no observed cytotoxicity.”

Because a score of ≤2 is considered an acceptable level of cytotoxicity,all materials tested in this experiment were determined to have anacceptable level of cytotoxicity.

Example 7—In Vivo Toxicity Analysis for Exemplary Hydrogel

The left eye in each of three rabbits was subjected to intravitrealinjection of the hydrogel premix from Example 2. The right eye in eachof the three rabbits did not receive treatment and, therefore, was usedas a “control.” The rabbits' eyes were examined after intravitrealinjection on the day of injection, and then again at 1, 2, 3, and 7 daysafter intravitreal injection. No evidence of inflammation, highintraocular-pressure in the eye, formation of cataracts, or retinalchange was observed clinically. Additionally, histopathologic analysisof the rabbits' retinal tissue showed normal retinal architecture. FIG.7 is an illustration of histopathologic analysis of rabbit retinaltissue obtained on day 7 after intravitreal injection for rabbit eyesthat (i) had received hydrogel premix (“hydrogel-treated eye”) and (ii)had not received hydrogel premix (i.e., “control”).

Example 8—Use of Exemplary Hydrogel In Vitrectomy in Rabbit Eyes

Three rabbits were subjected to a 25 gauge pars plana vitrectomy to theleft eye using hydrogel premix from Example 2. The procedure entailedpeeling of the posterior hyaloid face, fluid air exchange, and theninjecting the hydrogel premix into the eye of the rabbits. The rabbitswere analyzed one week after completing the foregoing procedure. It wasdetermined that all rabbits had normal intraocular pressure, hadwell-perfused optic nerves, and were healthy. Intraocular pressurevalues for the rabbits' eyes are presented in Table 2 below.

TABLE 2 Intra-ocular Pressure One Day Intra-ocular Pressure Seven AfterInjection of Hydrogel Days After Injection of Subject (mmHg) Hydrogel(mmHg) Identification Control Hydrogel- Control Hydrogel- No. EyeTreated Eye Eye Treated Eye 1 13 14 9 10 2 12 13 8 10 3 19 15 16 10

FIG. 8 provides an illustration of a rabbit eye 1 day after a vitrectomywas performed using the hydrogel according to this procedure. Asdepicted in FIG. 8 , the rabbit eye was observed to have a normalappearance of the posterior pole.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A method of providing a retinal tamponade in aneye of a subject, the method comprising: a. contacting retinal tissue inthe eye of the subject with an effective amount of a nucleo-functionalpolymer and an electro-functional polymer; and b. allowing thenucleo-functional polymer and electro-functional polymer to react toform a hydrogel in the eye, which hydrogel forms the retinal tamponade;wherein the nucleo-functional polymer is a biocompatible polymercomprising poly(vinyl alcohol) containing a plurality of thio-functionalgroups —R¹—SH, wherein R¹ is an ester-containing linker, and theelectro-functional polymer is a biocompatible polymer comprisingpoly(ethylene glycol) containing at least one thiol-reactive group. 2.The method of claim 1, wherein the retinal tamponade is provided in theeye of a subject having undergone a vitrectomy, having a rhegmatogenousretinal detachment, having tractional retinal detachment, or havingserous retinal detachment.
 3. The method of claim 1, wherein the retinaltamponade is provided in the eye of a subject having undergone afluid-air exchange.
 4. The method of claim 3, wherein the eye is anair-filled eye.
 5. The method of claim 1, wherein the hydrogel is formedon the retinal tissue.
 6. The method of claim 1, wherein the hydrogelforms a retinal tamponade by contacting and supporting an area ofphysical discontinuity in the retina.
 7. The method of claim 6, whereinthe physical discontinuity in the retina comprises a detachment, tear,break, hole, or combination thereof, in the retinal tissue.
 8. Themethod of claim 1, wherein the nucleo-functional polymer and theelectro-functional polymer are administered separately as liquid aqueouspharmaceutical compositions or together as a single, liquid aqueouspharmaceutical composition to the eye of the subject.
 9. The method ofclaim 8, wherein the separate liquid aqueous pharmaceutical compositionsor single liquid aqueous pharmaceutical composition has a pH in therange of about 7.2 to about 7.6.
 10. The method of claim 1, wherein thehydrogel has a refractive index in the range of from about 1.2 to about1.5.
 11. The method of claim 1, wherein the hydrogel has a transparencyof at least 95% for light in the visible spectrum when measured throughhydrogel having a thickness of 2 cm.
 12. The method of claim 1, whereinthe hydrogel has a gelation time of less than about 10 minutes.
 13. Themethod of claim 1, wherein the hydrogel undergoes completebiodegradation from the eye of the subject within about 3 days to about7 days, about 2 weeks to about 8 weeks, or about 4 months to about 6months, or within 12 months or 24 months.
 14. The method of claim 1,wherein the hydrogel has a biodegradation half-life in the range of fromabout 1 week to about 3 weeks or from about 8 weeks to about 15 weekswhen disposed within the eye.
 15. The method of claim 1, wherein thehydrogel generates a pressure within the eye of less than 25 mmHg. 16.The method of claim 1, wherein the nucleo-functional polymer has aweight-average molecular weight in the range of from about 500 g/mol toabout 1,000,000 g/mol; and wherein the electro-functional polymer has aweight-average molecular weight in the range of from about 500 g/mol toabout 1,000,000 g/mol.
 17. The method of claim 1, wherein the mole ratioof (i) thio-functional groups —R¹—SH to (ii) the at least onethiol-reactive group is in the range of 10:1 to 1:10, 5:1 to 1:1, or 2:1to 1:1.
 18. The method of claim 1, wherein R¹—SH is —OC(O)—(C₁-C₆alkylene)—SH.
 19. The method of claim 1, wherein the poly(ethyleneglycol) is linear, branched, a dendrimer, or multi-armed.